Syddansk Universitet
Colorectal cancer mortality 10 years after a single round of guaiac faecal occult blood
test gFOBT screening
Bjerrum, Andreas; Andersen, Ole; Fischer, Anders; Lindebjerg, Jan; Lynge, Elsebeth
Published in:
B M J Open Gastroenterology
DOI:
10.1136/bmjgast-2016-000120
Publication date:
2016
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Citation for pulished version (APA):
Bjerrum, A., Andersen, O., Fischer, A., Lindebjerg, J., & Lynge, E. (2016). Colorectal cancer mortality 10 years
after a single round of guaiac faecal occult blood test gFOBT screening: experiences from a Danish screening
cohort. B M J Open Gastroenterology, 3, [e000120]. DOI: 10.1136/bmjgast-2016-000120
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Colorectal cancer
Colorectal cancer mortality 10 years
after a single round of guaiac faecal
occult blood test (gFOBT) screening:
experiences from a Danish screening
cohort
Andreas Bjerrum,1 Ole Andersen,1 Anders Fischer,2 Jan Lindebjerg,3
Elsebeth Lynge,1
To cite: Bjerrum A,
Andersen O, Fischer A, et al.
Colorectal cancer mortality
10 years after a single round
of guaiac faecal occult blood
test (gFOBT) screening:
experiences from a Danish
screening cohort. BMJ Open
Gastro 2016;3:e000120.
doi:10.1136/bmjgast-2016000120
Received 1 September 2016
Revised 3 October 2016
Accepted 18 October 2016
1
Department of Public Health,
University of Copenhagen,
Copenhagen K, Denmark
2
Copenhagen University
Hospital Herlev, Herlev,
Denmark
3
Department of Pathology,
Vejle Hospital, Vejle,
Denmark
Correspondence to
Dr Andreas Bjerrum;
[email protected]
ABSTRACT
Background: In Denmark, colorectal cancer (CRC) is
the third most frequent cancer. Randomised trials have
shown that guaiac faecal occult blood test (gFOBT)
screening can reduce CRC mortality, but a recent large
randomised study from Finland did not find any effect.
A feasibility study was carried out in Denmark in
2005–2006 where residents aged 50–74 years in 2
Danish counties were invited once to participate in
gFOBT screening. We used the unique Danish registers
to assess the impact of gFOBT screening in this group
on CRC incidence and mortality.
Methods: In this cohort study, we followed a group
comprising 166 277 individuals invited to screening
and a reference group comprising the remaining
1 240 348 Danes of the same age. We linked the
Danish population and health service registers to
obtain information about colonoscopies,
polypectomies, incident CRC and cause of death.
Results: After a median follow-up time of 8.9 years,
the CRC mortality was significantly lower in the
screening group than in the reference group with an
adjusted HR (aHR) of 0.92 (95% CI 0.86 to 0.99),
while the aHR for all-cause mortality was 0.95 (95% CI
0.94 to 0.96). For screening participants, the aHR for
CRC mortality and all-cause mortality was 0.72 (0.64
to 0.80) and 0.59 (0.57 to 0.60), respectively.
Conclusions: About 10 years after a single round of
gFOBT screening, we found a significant 8% deficit in
CRC mortality in the screening group compared with
other Danes. We found almost the same deficit in allcause mortality, and on this basis, it is not possible to
conclude that one screening round had an effect on
CRC mortality. Our study indicated that close monitoring
of the outcome of CRC screening is warranted.
INTRODUCTION
In Denmark, colorectal cancer (CRC) is the
third most frequent cancer for men and
women aged 50–74 years with age-standardised
incidences of 160 and 126 cases per 100 000
Summary box
What is already known about this subject?
▸ Randomised controlled trials with faecal occult
blood based screening have shown a reduction
in colorectal cancer mortality.
▸ Based on the favourable outcomes, colorectal
cancer screening is now widely implemented.
▸ However, no reduction in colorectal cancer mortality was found in a large Finnish randomised
health service study, though with a relatively
short follow-up time.
What are the new findings?
▸ We report long term follow-up from a Danish
screening feasibility study including one round
of faecal occult blood based screening.
▸ The population invited to screening had an 8%
lower colorectal cancer mortality and a 5% lower
all-cause mortality as compared with other
Danes.
▸ As the deficits in colorectal cancer and all-cause
mortality were almost equal, it is not possible to
conclude that one screening round had an effect
on colorectal cancer mortality.
How might it impact on clinical practice in
the foreseeable future?
▸ Our study indicates that close monitoring of the
outcome of colorectal cancer screening is
warranted.
(Nordic Standard Population, 2007–2011).1
Several randomised trials have shown that
guaiac faecal occult blood test (gFOBT)
screening can reduce CRC mortality2–5 and
CRC screening has been implemented in
several countries to detect and treat CRC
before the disease becomes symptomatic.
In a recent large randomised study from
Finland, Pitkäniemi et al6 did not detect any
effect of gFOBT screening on CRC mortality.
Bjerrum A, Andersen O, Fischer A, et al. BMJ Open Gastro 2016;3:e000120. doi:10.1136/bmjgast-2016-000120
1
Open Access
In contrast to the previous randomised trials,7 the
Finnish study was designed as a randomised health
service study embedded in the routine health services
and the authors argued that this was characterised by
variation in available resources; a population that may
have been less motivated; and health experts that were
possibly not as devoted and did not follow guidelines as
strictly as in scientific trials.6
As an input to the Danish debate on a possible national
CRC screening programme, a feasibility study within the
routine healthcare was carried out in 2005–2006.8 9
Residents aged 50–74 years in two Danish counties were
invited once to participate in the screening performed
with gFOBT. Colonoscopy or alternatively colonography
was offered if the screening test was positive. From 1
January 2014, a nationwide screening programme was
implemented in Denmark following the same scheme,
but based on the faecal immunochemical test (FIT).
The unique Danish population and health registers
allowed us to follow-up the population invited for the
feasibility study for 10 years to assess the impact of the
screening on CRC incidence and mortality in a routine
healthcare setting.
METHODS
Study design and study population
In this population-based cohort-study, we included all
Danish residents born between 3 August 1930 and 2
August 1955 and living in Denmark on 2 August 2005.
The screening group comprised persons invited to CRC
screening, that is, all inhabitants in Vejle county and a
random sample of approximately half of the inhabitants
in the Copenhagen county, while the reference group
comprised the other Danes.
Individual invitation dates were known for the screening group. We used the invitation scheme from the
screening group to assign pseudoinvitation dates to
persons in the reference group. In the following, we use
the term ‘invitation date’ for the ‘true invitation dates’
in the screening group and ‘pseudoinvitation dates’ in
the reference group.
Based on unique personal identification, we linked
each person with the Danish Cancer Register to obtain
information about incident CRC cases, the National
Patient Register for diagnoses and hospital procedures
including colonoscopies and polypectomies, the Health
Service Register for private sector colonoscopies and
polypectomies, and the Death Cause Register.
We excluded persons who died or emigrated before
the invitation date, were diagnosed with CRC (ICD10:
C18/C19/C20/C21) or inflammatory bowel disease
(ICD8: 563.01/563.02/563.09/563.19 and ICD10: K50/
K51) prior to invitation; or persons who underwent colonoscopy, sigmoidoscopy or any invasive colon or anorectal procedure in the period from 2 years before the
screening programme started, that is, 2 August 2003,
until the invitation date. Data linkage identified a
number of persons excluded from screening for
unknown reasons. These persons were excluded from
the screening group in our analyses. We performed sensitivity analyses to assess the impact of this group on our
results.
Screening process
Persons invited to the screening programme received a
gFOBT kit per mail. The letter included an invitation
describing the background and purpose of screening,
instructions for sampling and a prepaid return envelope.
Participants with a positive gFOBT were notified by
mail and invited to colonoscopy or alternatively
colonography.
In Vejle County, colonoscopies were performed at
three selected hospitals. Diagnostic biopsy and polypectomy was performed as part of the follow-up procedure.
In Copenhagen County, colonoscopies were performed
in hospitals and private clinics. Patients with many adenomas were referred to hospitals for further diagnostic
procedures and polypectomy. Postpolypectomy surveillance was not specified in the feasibility study, but undertaken according to the clinical practice at the respective
hospitals.
Definitions and statistical analyses
Persons were followed from the invitation date to date of
death, emigration or 31 December 2014, whichever
came first. The first colonoscopy performed after a positive gFOBT was defined as the baseline colonoscopy, as
Figure 1 Inclusion and exclusion in the study population.1 The same person may fall for more than one criterion for exclusion.
2
Bjerrum A, Andersen O, Fischer A, et al. BMJ Open Gastro 2016;3:e000120. doi:10.1136/bmjgast-2016-000120
Open Access
long as it was within 90 days of invitation. CRC-cases
diagnosed within 180 days after the baseline colonoscopy
were categorised as screen-detected CRC.
We calculated incidence-based CRC mortality rates
for the screening and reference groups, including only
CRC deaths in cases diagnosed after the invitation
date. The multivariate Cox regression was used to calculate HRs adjusted for sex and age (aHR) for CRC
incidence, CRC mortality and all-cause mortality.
Table 1 Characteristics of the study population
Population
Person time
(years)
Sex
Female
Male
Median age at
invitation
50−54 years
55−59 years
60−64 years
65−69 years
70−74 years
74+ years
Screening
group
Reference
group
p
Value
166 277
1 393 131
1 240 348
10 358 902
48.9%
51.1%
60.6
49.5%
50.5%
60.5
<0.01
21.8%
25.2%
22.9%
16.7%
13.0%
0.4%
22.0%
25.4%
22.8%
16.3%
12.8%
0.8%
0.10
0.08
0.24
<0.01
<0.01
<0.01
Gender-based analyses were adjusted for age, and
persons in the screening group were compared with
persons in the reference group of the same gender. We
tested for interactions and proportionality based on
Schoenfeld residuals.
We estimated the excess mortality rate by dividing the
excess number of deaths observed in persons with CRC
by the total number of person-years in the screening
group and reference group (stratified by sex and age).
The excess mortality rate ratio was calculated according
to procedures described by van Leeuwen et al.10
All statistical analyses were conducted with Stata
V.14.1.
Ethics
The Danish Data Protection Agency approved the
linkage between the registers in this study ( J.-no.
2015-41-4012). The study was not subject to approval by
the Ethics Committee since data collection did not
involve patient contact or access to patients’ medical
records.
0.06
The screening group includes persons invited to colorectal cancer
screening in Vejle and Copenhagen counties. The reference group
includes persons in the rest of Denmark in the same age group.
RESULTS
We identified 1 524 259 persons aged 50–74 years and
living in Denmark on 2 August 2005. A total of 117 634
persons were excluded based on predefined criteria
(figure 1). Consequently, this study included 1 406 625
persons divided into the screening group of 166 277,
and a reference group of 1 240 348. The median
follow-up time was 8.9 years for the screening group and
Table 2 Comparison between the screening group from Vejle and Copenhagen counties and the intervention group from the
randomised controlled trial in Funen, Denmark5
Number invited
Participants
Positive FOBT
Colonoscopy
Colorectal cancer
Screening group Vejle and
Copenhagen counties
Number
% of group above
Intervention group, randomised
controlled trial, Funen, Denmark
Number
% of group above
166 277
80 563
1924
1741
155
30 970
20 672
215
203
37
NR
48.5%
2.4%
90.5%
8.9%
NR
66.7%
1.0%
94.4%
18.2%
Table 3 Percentage and number of persons with colonoscopies and polypectomy
Persons with
Persons with
Persons with
Persons with
Persons with
Persons with
colonoscopy
colonoscopy≤2 years from invitation
colonoscopy >2 years from invitation
polypectomy
polypectomy ≤2 years from invitation
polypectomy >2 years from invitation
Screening group
No.
Percentage*
Reference group
No.
Percentage†
30 264
7513
25 432
7157
1808
5656
206 125
42 886
179 282
46 383
8391
39 364
18.2
4.5
15.3
4.3
1.1
3.4
16.7
3.5
14.5
3.7
0.7
3.2
*Percentage of 166 277 persons in the screening group.
†Percentage of 1 240 348 persons in the reference group.
Bjerrum A, Andersen O, Fischer A, et al. BMJ Open Gastro 2016;3:e000120. doi:10.1136/bmjgast-2016-000120
3
4
NR
<0.01
<0.01
<0.01
<0.01
0.65
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
to 0.96
to 0.93
to 0.60
to 1.29
to 1.02
to 0.61
to 1.38
to 0.98
to 0.96
to 0.60
to 1.33
NR
0.94
0.90
0.56
1.23
0.98
0.57
1.32
0.94
0.93
0.57
1.29
1
0.95
0.91
0.58
1.26
1
0.59
1.35
0.96
0.95
0.59
1.31
164 346
20 981
10 169
3405
6764
10 812
3018
7794
11 944
9037
6423
14 558
NR
0.03
0.37
<0.01
0.03
0.02
<0.01
0.17
0.07
0.19
<0.01
0.01
to 0.99
to 1.06
to 0.90
to 1.32
to 0.98
to 0.77
to 1.24
to 1.01
to 1.04
to 0.80
to 1.23
NR
0.86
0.87
0.67
1.02
0.80
0.55
0.96
0.83
0.83
0.64
1.03
1
0.92
0.96
0.77
1.16
0.89
0.65
1.09
0.91
0.93
0.72
1.12
6431
796
419
178
241
377
131
246
439
357
309
487
NR, not relevant.
*Compared with the reference group males.
†Compared with the reference group females.
Reference group
Screening group
Vejle County
Screening participants
Non-responders
Copenhagen County
Screening participants
Non-responders
Males*
Females†
All screening participants
All non-responders
22 216
2794
1440
732
708
1354
556
798
1543
1251
1288
1506
1
0.94
0.95
0.92
0.98
0.92
0.81
1.03
0.94
0.93
0.87
1.00
NR
0.90 to
0.90 to
0.85 to
0.91 to
0.87 to
0.74 to
0.96 to
0.89 to
0.88 to
0.82 to
0.95 to
0.97
1.00
0.99
1.05
0.98
0.88
1.10
1.00
0.98
0.92
1.06
NR
<0.01
0.05
0.03
0.56
<0.01
<0.01
0.49
0.05
0.01
<0.01
0.93
All-cause mortality
No.
aHR
95% CI
p Value
95% CI
CRC mortality
No.
aHR
p Value
95% CI
CRC incidence
No.
aHR
Table 4 HRs for colorectal cancer (CRC) incidence and mortality and all-cause mortality, adjusted for sex and age
the reference group with an IQR of 208 and 210 days for
the screening group and reference group, respectively.
The longest follow-up was 9.4 years in both groups.
The proportion of women was marginally lower in the
screening group than in the reference group (table 1).
Moreover, in the screening group, there was a small but
significant over-representation of persons aged 65–
74 years, and a marginally smaller proportion of persons
aged 75 years and above.
In the screening group, 80 563 persons (48.5%)
returned a stool sample. Among those, 1924 (2.4%) had
a positive gFOBT, of whom 1737 (90.3%) underwent colonoscopy. Among those, 155 (8.9%) patients were diagnosed with CRC (table 2). About 4.5% in the screening
group underwent colonoscopy within the first 2 years
after invitation compared with 3.5% in the reference
group (table 3). More than 2 years after the invitation,
the two groups had almost the same use of colonoscopies. Polypectomy was performed in 4.3% of the
screening group compared with 3.7% in the reference
group. Within the first 2 years after invitation, 1.1% from
the screening group underwent polypectomy compared
with 0.7% in the reference group.
The CRC incidence during the follow-up period was
significantly lower in the screening group than in
the reference group (aHR 0.94, 95% CI 0.90 to 0.97)
(table 4). In the screening group, CRC incidence rose
quickly within the first year after invitation due to
screen-detected cases. After ∼3.5 years, the curve for the
screening group crossed the curve for the reference
group (figure 2).
The CRC mortality during the follow-up period was
significantly lower in the screening group than in the
reference group (aHR 0.92, 95% CI 0.86 to 0.99), with
the deficit coming from the Copenhagen part of the
screening group (aHR for Vejle 0.96, 95% CI 0.87 to
1.06; aHR for Copenhagen 0.89, 95% CI 0.80 to 0.98)
(table 4). We did not observe any difference between
men and women. The all-cause mortality was also
significantly lower in the screening group than in the
reference group (aHR 0.95, 95% CI 0.94 to 0.96), with
the deficit coming from Vejle county (aHR for Vejle
0.91, 95% CI 0.90 to 0.93; aHR for Copenhagen 1.00,
95% CI 0.98 to 1.02). The deficit in Vejle was seen
from the very beginning of the follow-up period
(figure 3).
Perprotocol analysis showed that screening participants had lower CRC incidence (aHR 0.94, 95% CI 0.90
to 0.97), lower CRC mortality (aHR 0.72, 95% CI 0.64 to
0.80) and substantially lower all-cause mortality (aHR
0.59, 95% CI 0.57 to 0.60) (table 4). Non-responders
had significantly increased CRC mortality (aHR of 1.12,
95% CI 1.03 to 1.23) and all-cause mortality (aHR 1.31,
95% CI 1.29 to 1.33).
The excess mortality rate ratio due to CRC for the
screening group was 0.93 (95% CI 0.84 to 1.02); 0.93
(95% CI 0.82 to 1.07) for Vejle County and 0.92 (95%
CI 0.80 to 1.06) for Copenhagen County.
p Value
Open Access
Bjerrum A, Andersen O, Fischer A, et al. BMJ Open Gastro 2016;3:e000120. doi:10.1136/bmjgast-2016-000120
Open Access
Sensitivity analyses to assess the influence of 3757
persons, who were excluded from screening in the feasibility study for unknown reasons, showed that their
inclusion in the analyses did not influence our results
significantly (data not shown).
Figure 2 Cumulative colorectal cancer incidence in persons
from Vejle and Copenhagen counties invited to screening and
in persons from the rest of Denmark.
DISCUSSION
Approximately 10 years after a single round of gFOBT
screening for CRC, we found a significant 8% lower
incidence-based CRC mortality in the invited screening
group than in the reference group of other Danes. This
could point to a beneficial impact of the screening. It
should, however, be taken into account that the invited
screening group did not represent a random sample of
the Danish population. The all-cause mortality was 5%
lower in the invited screening group than in the reference group. As the difference in the deficits of 8% for
CRC mortality and 5% for all-cause mortality is marginal, it is not possible to attribute the reduced CRC
mortality to one screening round alone. The uncertainty
in these numbers came from the Vejle part of the
invited screening group, as this group clearly represented a healthier subpopulation than the rest of Danes.
One may argue that the Copenhagen part of the invited
screening group would give a clearer picture of the
screening effect as this group had a 11% deficit in CRC
mortality and an all-cause mortality similar to that of
other Danes. This is, however, a subgroup analysis not
originally planned for.
Figure 3 Cumulative colorectal cancer mortality and all-cause mortality in persons in Vejle and Copenhagen counties invited to
screening and in persons in the rest of Denmark.
Bjerrum A, Andersen O, Fischer A, et al. BMJ Open Gastro 2016;3:e000120. doi:10.1136/bmjgast-2016-000120
5
Open Access
Screening participants represented a selected group.
When compared with the reference group, participants
had a 41% lower all-cause mortality, while nonparticipants had a 31% higher all-cause mortality. This
highlights the problem of inequitable uptake of screening services; those who participate are healthier than
those who do not. Since we could not control for selective participation in the HRs for CRC mortality, the
reported deficit in CRC mortality among participants
should be interpreted with caution.
When compared with the earlier randomised controlled trial on gFOBT CRC screening in Funen,
Denmark, the participation in the feasibility study was
low, 49% when compared with 67%, though the CRC
detection rates were identical, 1.9 per 1000 participants
in the feasibility study and 1.8 in the trial.5 Within the
group invited to screening, 18% had at least one colonoscopy during the ∼10 years of follow-up. Colonoscopy
rate was higher in the screening group within the first
2 years, but equal to findings in the reference group the
following years. This may be due to cancer awareness
within the general population and among general practitioners in Denmark.
The screen-detected cases represented only 155 out of
the 2794 CRC cases in the group invited to screening.
The remaining 2639 CRC cases were detected within
the routine healthcare system with prognosis comparable to cases detected in the reference group. The polypectomy rate within the first 2 years after invitation was
higher in the screening group than in the reference
group. Colorectal adenomas may be cancer precursors,11
and there is evidence that detection and removal of
these lesions may prevent cancers.12 This is expected to
have contributed to the slightly lower CRC incidence in
the screening group than in the reference group; 2794
observed cases vs 2972 (=2794/0.94 aHR for CRC incidence) expected cases, resulting in a deficit of 178
cases. The potential effect of the one-round screening
on the CRC mortality was therefore based on the relatively few cases detected at screening or prevented
due to polypectomy. This finding clearly illustrates the
need for repeated testing in faecal occult blood-based
screening programmes.
van Leeuwen et al10 have shown that, in prostate
cancer screening, disease-specific mortality has been
systematically underestimated due to risk of misclassification of cause-of-death. The authors argue that estimation
of the excess mortality is of additional value to a diseasespecific mortality analysis since it measures the effect of
screening in the presence of all competing risks. We did
not notice any discrepancy between disease-specific mortality and excess mortality in our data, which indicates
high data quality and accuracy.
It was a strength of this study that we could individually follow all persons invited to screening in 2005/2006
for a period of ∼10 years. It was furthermore a strength
that linkage to the Danish Cancer Register allowed us to
calculate incidence-based CRC mortality. It was a
6
weakness of this observational study that we were not
able to control for prescreening differences in health
status between the screening counties and the rest of
Denmark. This is in contrast to the Danish studies on
the effect of mammography screening on breast cancer
mortality,13 14 where calendar period and region were
controlled for in the analysis. The study relied on health
service register data submitted by health providers.
While the quality of register data is considered to be
high,15 we did encounter some discrepancies in the
register data on colonoscopies and polypectomies,
which may have introduced bias.
Biennial gFOBT CRC screening has been introduced
in many countries based on the results from the randomised controlled trials in Minnesota,2 Göteborg,3
Nottingham4 and Funen.5 A systematic review from the
US Preventive Services Task Force showed a significant
reduction in CRC mortality after 11–30 years (relative
risk (RR) 0.91, 95% CI 0.84 to 0.98) and after 30 years
(RR 0.78, 95% CI 0.65 to 0.93).7 A Finnish populationbased gFOBT CRC screening programme was introduced as a public health trial, where a random 50% of
each birth cohort was invited.6 The results of the
Finnish study were too new to be included in the US systematic review. However, after accumulation of 180 000
persons invited to screening, and with a follow-up of on
average 4.5 years, there was no impact of the screening
on CRC mortality (RR 1.04, 95% CI 0.84 to 1.28).6 In
contrast to the Finnish study, we did not observe any difference in screening effect between men and women. A
4.5 average years of follow-up is a short time, but the
Finnish results, together with the more limited data
from this Danish feasibility study, nevertheless indicate
that close monitoring of the outcome of the ongoing
CRC screening programmes is warranted. The combined
effect of increased cancer awareness, good access to colonoscopy and accelerated cancer care pathways may
improve early detection and treatment for CRC and
diminish the potential impact of gFOBT screening. The
FIT is more acceptable for participants than the gFOBT,
and it also has higher sensitivity for faecal blood.16 17
For this reason, many countries, including Denmark,
now use FIT in their CRC screening programmes.
CONCLUSION
An ∼10 years’ follow-up of a one-round CRC screening
in a Danish feasibility study showed an 8% deficit in
CRC mortality when compared with Danes in the rest of
the country. There was however almost the same deficit
in the all-cause mortality. On this basis, it is not possible
to conclude that screening in the feasibility study had an
effect on CRC mortality. Our results, together with new
results from the large Finnish CRC screening programme, indicate that close monitoring of the outcome
of CRC screening programmes is warranted.
Acknowledgements The authors thank Søren Nymand Lophaven for
statistical advice.
Bjerrum A, Andersen O, Fischer A, et al. BMJ Open Gastro 2016;3:e000120. doi:10.1136/bmjgast-2016-000120
Open Access
Contributors All authors were involved in conceptualising the study and
approved the final version of the manuscript. AB and EL designed the study
and statistical analyses. AB and JL collected data. AB cleaned and analysed
the data. AB and EL drafted the paper. All authors critically revised the
manuscript.
Funding This research was supported by a grant of 25000 DKK from
Copenhagen University Hospital, Herlev, to cover data retrieval from the
Danish Health Registers. The research received no other funding from the
public, commercial or not-for-profit sectors.
5.
6.
7.
8.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
9.
Data sharing statement No additional data are available.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/4.0/
10.
11.
12.
13.
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